University of Groningen
Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma
patients in the Netherlands
Verkouteren, Babette J. A.; Wakkee, Marlies; Reyners, An K. L.; Nelemans, Patty; Aarts,
Maureen J. B.; Racz, Emoke; Terra, Jorrit B.; Devriese, Lot A.; Alers, Robert-Jan; Kapiteijn,
Ellen
Published in:
British Journal of Cancer
DOI:
10.1038/s41416-020-01220-w
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Publication date:
2021
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Verkouteren, B. J. A., Wakkee, M., Reyners, A. K. L., Nelemans, P., Aarts, M. J. B., Racz, E., Terra, J. B.,
Devriese, L. A., Alers, R-J., Kapiteijn, E., van Doorn, R., Bekkenk, M. W., Reinders, M. G. H. C., & Mosterd,
K. (2021). Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma
patients in the Netherlands: a retrospective cohort study. British Journal of Cancer.
https://doi.org/10.1038/s41416-020-01220-w
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ARTICLE
Clinical Study
Eight years of experience with vismodegib for advanced and
multiple basal cell carcinoma patients in the Netherlands: a
retrospective cohort study
Babette J. A. Verkouteren 1,2, Marlies Wakkee3, An K. L. Reyners4, Patty Nelemans5, Maureen J. B. Aarts6, Emőke Rácz7, Jorrit B. Terra8,
Lot A. Devriese9, Robert-Jan Alers10, Ellen Kapiteijn11, Remco van Doorn12, Marcel W. Bekkenk13, Marie G.H.C. Reinders1,2and
Klara Mosterd1,2
BACKGROUND: Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC
(mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib
for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands.
METHODS: A retrospective cohort study that included all patients≥18 years with histologically proven basal cell carcinoma that
received≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands.
RESULTS: In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95%
confidence interval (CI), 7.5–22.6) for laBCC, 11.7 (95% CI, 5.2–17.5) for mBCC and 19.1 (95% CI, 7.4–20.2) for BCNS. Larger laBCCs
were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p= 0.02). Of all BCNS
patients, 63% received≥2 treatment sequences with vismodegib; all achieved partial responses.
CONCLUSIONS: Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.
British Journal of Cancer https://doi.org/10.1038/s41416-020-01220-w
BACKGROUND
Basal cell carcinoma (BCC) is the most common skin cancer
worldwide.1Therapeutic options vary from non-invasive therapies
to local radiotherapy and surgery.2 However, if a BCC stays
untreated, it can develop into an advanced BCC (aBCC), comprising locally advanced BCC (laBCC) and metastatic BCC (mBCC). Surgery or radiotherapy is not always an option for the treatment of aBCCs. In 2012, the Phase 2 ERIVANCE BCC trial investigated the efficacy and safety of vismodegib, the first-in-class molecule for targeted therapy for aBCCs that are not suitable
for surgery and/or radiotherapy.3 Vismodegib inhibits the
oncogenic protein smoothened (SMO), a downstream signal of the hedgehog pathway that plays an important role in the pathogenesis of BCC. Mutations in the hedgehog pathway are
found in the majority of BCCs.4An efficacy analysis of 96 patients
in the ERIVANCE trial showed a median investigator-assessed
progression-free survival (PFS) of 9.3 months (95% confidence
interval (CI), 7.4–16.6) for those with mBCC and 12.9 months (95%
CI, 10.2–28.0) for those with laBCC.3Based on the results of this
trial and under priority review as afirst-in-class molecule, targeted
therapy with vismodegib was registered for the treatment of
laBCC and mBCC in the Netherlands.5Another large Phase 2 trial
assessed the safety of vismodegib (SafeTy Events in VIsmodEgib,
STEVIE). The efficacy analysis of that trial included 1192 patients
and showed a median investigator-assessed PFS of 13.1 months (95% CI, 12.0–17.7) for those with mBCC and 23.2 months (95% CI,
21.4–26.0) for those with laBCC.6
Of all patients, 98% experienced at least one adverse event, with the most frequently observed adverse events being muscle spasms, alopecia, dysgeusia,
decreased appetite, decreased weight, and asthenia.6 In both
the ERIVANCE BCC and STEVIE trials, only dose interruption of
4–8 weeks was accepted to recover from toxic effects and
Received: 17 June 2020 Revised: 25 November 2020 Accepted: 2 December 2020
1
Department of Dermatology, Maastricht University Medical Center, Maastricht, The Netherlands;2
GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands;3
Department of Dermatology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands;4
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;5
Department of Epidemiology, Maastricht University, Maastricht, The Netherlands;6Department of Medical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands;7Department of Dermatology, University Medical Center Groningen, Groningen, The Netherlands;8
Department of Dermatology, Isala Dermatologic Center, Zwolle, The Netherlands;9
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands;10Department of Gynecology, Maastricht University Medical Center, Maastricht, The Netherlands;11Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands;12
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands and13
Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands
Correspondence: Babette J. A. Verkouteren (babette.verkouteren@mumc.nl)
different treatment schedules were not allowed.3,7Some patients
need long-term treatment with vismodegib and an intermittent treatment schedule could possibly optimise the balance between
benefit and side effects. This seems especially relevant in patients
with basal cell nevus syndrome (BCNS), as BCCs will keep on developing in these patients during their entire lives. Therefore, the multiple basal cell carcinomas (MIKIE) trial compared two different intermittent dosing regimens for vismodegib in patients
with either BCNS or high-frequency BCC (HF-BCC) patients.8Both
schedules showed similar response rates and adverse events rates;
however, intermittent dosing was associated with fewer grade≥3
treatment-emergent adverse events (TEAEs) compared to the
STEVIE trial.8The median duration of treatments in the MIKIE trial
was 71.4 and 68.4 weeks depending on the dosing schedule, compared to 36.4 weeks for laBCC patients and 52.0 weeks for mBCC patients treated with the regular dosing schedule of 150 mg
daily in the STEVIE trial.7,8 Unfortunately, extensive information
about the indication, use, safety and (predictors of) effectiveness
of vismodegib is still sparse.9 This study presents effectiveness,
safety and the treatment course of all patients with aBCC or multiple BCCs who were treated with vismodegib in the Nether-lands between July 2011 to September 2019.
METHODS
Study design and patients
This retrospective, multicentre, longitudinal cohort study included all patients treated with vismodegib for aBCC or multiple BCCs in the Netherlands from July 2011 till 9 September 2019. In the Netherlands, vismodegib is only prescribed in seven academic medical hospitals (verified by contacting insurance companies), and all patients were gathered from these centres. All patients
were aged ≥18 years, had a histologically proven BCC and
received at least one dose of vismodegib. All indications for vismodegib treatment in BCC were included; laBCC, mBCC, multiple BCCs in BCNS and in non-BCNS patients. Vismodegib
was either started in a clinical trial setting (STEVIE, n= 21 times, or
MIKIE, n= 8 times) or in daily practice (n = 92 times).7,8 A new
treatment sequence was defined as restarting vismodegib after a
break of at least 8 weeks. Under the supervision of a dermato-oncologist (K.M.), two investigators, B.J.A.V and R.-J.A., extracted
data from the electronic patient files and entered it into a
standardised Castor database. This study was approved with a waiver of informed consent by the Medical Ethics Committee of all participating centres.
Outcome measures
For the analysis on the effectiveness of vismodegib, the primary
endpoint was the median PFS after the start of the first
vismodegib prescription. Secondary endpoints were the differ-ence in median PFS between the clinical trial and daily practice patients, probability of response (partial and complete) and PFS at 1, 3, 6 and 12 months, median duration of (complete) response and median time to all response endpoints (the period after which 50% of patients had reached the endpoint of interest). Response and progression were measured according to
investigator-assessed clinical response as noted in the patient file. For the
indication of multiple BCCs in (non-)BCNS patients, progression
was defined as the development of new or recurrent BCCs. An
additional analysis was performed to evaluate which patient and tumour characteristics were associated with an increased
prob-ability for achieving a complete response in the first treatment
sequence. For this purpose, data were recorded on the duration of tumour presence, tumour size, histologic subtype, bone invasion, and previous therapy. Tumour measurement information was
gathered from patientfiles, clinical photographs of the tumour
and/or computed tomography or magnetic resonance imaging. Safety analysis included frequency, severity (measured according
to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) and reversibility of TEAEs.
Data analysis and statistical method
Categorical variables were presented as percentages with absolute numbers and continuous variables as median with
range, as appropriate. Time-to-event (Kaplan–Meier) analyses were
used to estimate the cumulative probability of an endpoint at
pre-specified follow-up periods as well as median time to endpoints.
The observation period of patients started at the date of first
treatment with vismodegib and ended at the date of first
documentation of response or progression or at the date of death, depending on the studied outcome. A log-rank test was used to calculate differences between clinical trial and daily practice patients. For the median duration of response, the
observation period started at the date offirst documentation of
response and ended at the date of first documentation of
progression. For the patients who had not experienced the event of interest, observations were censored at the date of the last tumour assessment. Effectiveness analyses were performed on the first treatment sequence data. To evaluate characteristics asso-ciated with increased probability for achieving the complete
response in thefirst sequence, univariable Cox regression analyses
were performed and hazard ratios with 95% confidence intervals
and P values were calculated. The variables with a significant or
strong association (defined as at least halving of doubling of the
hazard ratio) were entered into a multivariable Cox regression analysis to evaluate the independent effect of these variables. P values <0.05 were considered to indicate the statistical significance. Statistical analyses were performed with IBM SPSS Statistics version 25 and STATA version 13.0.
RESULTS
Between July 2011 and September 2019, 80 patients were treated with vismodegib in seven centres in the Netherlands. Patient,
tumour and treatment characteristics can be found in Table 1.
Fifty-one patients were treated with only one sequence, 21 with only two, 3 with three, and 5 with four. Swimmer lane plots per
treatment indication can be seen in Fig. 1 and Kaplan–Meier
curves from time-to-event analyses in Fig.2and Table2.
LaBCC
A total of 48 patients received vismodegib for a laBCC,five of them
had BCNS. Tumours were located in the head and neck region in
83% (n= 40), on the trunk in 15% (n = 7) and on the extremities in
2% (n= 1). Median self-reported tumour presence was 6 years
(range, 0.3–20 years) and size was 5.0 cm (range, 1.0–30.0 cm), respectively. Thirty-seven tumours had an infiltrative component in the histologic sample (77%), nine were nodular (19%), and in two tumours (4%) this information was missing. Bone invasion was present in 16 of 48 tumours (33%). Of all 48 patients, 28 (58%) received at least one previous treatment for their tumour, mostly surgery or radiotherapy. At the start of vismodegib treatment, the
median age of the patients was 75.5 years (range, 36–98 years).
Effectiveness. Four patients received vismodegib intentionally as
neoadjuvant therapy and were therefore excluded leaving 44 patients for analysis. Median PFS was 10.3 months (95% CI,
7.5–22.6) for all 44 laBCC patients. There was no statistically
significant difference in median PFS between daily practice and
STEVIE trial patients (10.2 months (95% CI, 5.6–22.6) and
13.6 months (95% CI, 6.1–26.6), respectively (p = 0.39)). At
3 months after the start of vismodegib, the probability of partial
response was 94.6% (95% CI, 84.4–99.0) and probability of
complete response after 6 months of treatment was 33.9% (95% CI, 20.6–52.5), with a median duration of complete response of 10.3 months (95% CI, 4.5–22.1).
Eight years of experience with vismodegib for advanced and multiple basal. . . BJA Verkouteren et al.
The HRs from the multivariable analysis showed a significantly decreased probability of achieving a complete response in
larger tumours (HR 0.77 per increase in cm, p= 0.02), whereas
patients who participated in the STEVIE trial had a significantly
increased probability of achieving a complete response
com-pared to daily practice patients (HR 10.08, p < 0.01) (Table3). The
main reasons for treatment discontinuation were toxicity (n=
22) and tumour progression (n= 15). Retreatment with
vismo-degib (n= 12) led to a response in eight patients, six of them
eventually developed progressive disease again. Six patients died due to the laBCC.
MBCC
Eleven patients received vismodegib for metastasised BCC; none
of them had BCNS (Fig.1). One patient had been treated for the
primary laBCC with vismodegib and surgery 4.6 years before. Primary tumours were located in the head and neck region in
46% of patients (n= 5), on the trunk in 36% (n = 4) and on the
extremities in 18% (n= 2). The sites of metastases were: regional
lymph nodes 27% (n= 3), distant lymph nodes 9% (n = 1), lungs
55% (n= 6) and bones 18% (n = 2). Median self-reported
tumour presence was 5 years (range, 0.3–22 years) and size
was 14.5 cm in diameter (range, 4.0–22.0 cm). All tumours with
known subtype (n= 7) were infiltrative. At the start of treatment,
bone invasion was present in 55% of the patients (n= 6). Of all
mBCC patients, four did not receive any previous therapy and six
had received previous surgery for the primary BCC (Fig.1c). The
median age at the start of treatment was 70 years (range, 52–81
years).
Effectiveness. Of the 11 mBCC patients, one had previously been
treated for the mBCC with vismodegib abroad, leaving ten
patients for the effectiveness analysis. Median PFS was
11.7 months (95% CI, 5.2–17.5). At 3 months after the start of
Table 1. Patient, tumour and treatment characteristics.
laBCC, n= 48 mBCC,n= 11 BCNS,n= 19 Multiplenon-BCNS BCCs, n= 5 Sex Men, n (%) 24 (50%) 6 (55%) 12 (63%) 3 (60%) Women, n (%) 24 (50%) 5 (45%) 7 (37%) 2 (40%) Age at the start, median
(range), years 75.5 (36–98) 70 (52–81) 46(35–71) 77 (44-82) <65 years 11 (23%) 4 (36%) 18 (95%) 1 (20%) ≥65 years 37 (77%) 7 (64%) 1 (5%) 4 (80%) Caucasian, n (%) 48 (100%) 11 (100%) 19 (100%) 5 (100%) Self-reported presence of BCC
Median (range), years 6 (0.3–20) 5 (0.3–22) – – Unknown, n (%) 14 (29%) 3 (27%)
Basal cell nevus syndrome
Yes, n (%) 5 (10%) 0 (0%) 19 (100%) 0 (0%) No, n (%) 43 (90%) 11 (100%) 0 (0%) 5 (100%) Previous treatmenta None 20 (42%) 4 (36%) 0 (0%) 2 (40%) Surgery 21 (44%) 6 (55%) 19 (100%) 5 (100%) Radiotherapy 7 (15%) 1 (9%) 1 (5%) 2 (40%) Cryotherapy 2 (4%) 0 (0%) 3 (16%) 2 (40%) Curettage 1 (2%) 0 (0%) 3 (16%) 0 (0%) Photodynamic therapy 2 (4%) 0 (0%) 4 (21%) 2 (40%) 5-Fluorouracil cream 2 (4%) 0 (0%) 3 (16%) 1 (20%) Imiquimod cream 1 (2%) 0 (0%) 6 (32%) 0 (0%) Laser (type unknown) 0 (0%) 0 (0%) 2 (11%) 0 (0%)
Other 2 (4%) 1 (9%) 2 (11%) 0 (0%)
Site laBCC
Head and neck 40 (83%) 5 (46%) – –
Trunk 7 (15%) 4 (36%) – – Extremities 1 (2%) 2 (18%) – – Multiple sites – – 19 (100%) 5 (100%) Size laBCC Median (range) (cm) 5 (1–30) 14.5 (4–22) – – Unknown, n (%) 9 (19%) 5 (45%) – – Subtype laBCC Infiltrative 37 (77%) 7 (64%) – – Nodular 9 (19%) 0 (0%) – – Unknown 2 (4%) 4 (36%) – –
Bone invasion laBCC
Present, n (%) 16 (33%) 6 (55%) – –
Absent, n (%) 32 (67%) 5 (45%) – –
Site of metastasis
Regional lymph nodes – 3 (27%) – –
Distant lymph nodes – 1 (9%) – –
Lungs – 6 (55%) – –
Bones 2 (18%) – –
Duration offirst treatment sequence Median (range), months 6.4
(1.4–38.5) 7.5(1.6–18.5) 6.6(1.2–25.7) 14.4(2.8–16.8) Start dosage
150 mg daily 33 (69%) 11 (100%) 8 (42%) 2 (40%)
STEVIE 15 (31%) 0 6 (32%) 0
MIKIE 0 0 5 (26%) 3 (60%)
Short treatment interruptions
Yes, n (%) 6 (12%) 0 1 (5%) 0 No, n (%) 42 (88%) 11 (100%) 18 (95%) 5 (100%) Dosage change Yes, n (%) 3 (6%) 2 (18%) 1 (5%) 0 No, n (%) 45 (94%) 9 (82%) 18 (95%) 5 (100%) Sequencesb One 37 (77%) 9 (82%) 7 (37%) 4 (80%) Two 11 (23%) 2 (18%) 5 (26%) 1 (20%) Three 0 0 4 (21%) 0 Four 0 0 3 (16%) 0 Table 1. continued laBCC, n= 48 mBCC, n= 11 BCNS, n= 19 Multiple non-BCNS BCCs, n= 5 Median duration between
sequences, months (range)
6.0
(2.5–20.7) 6.9(2.0–11.8) 11.2(2.2–54.2) 3.0 (–) Clinical review frequency infirst sequence
Monthly 37 (77%) 8 (73%) 19 (100%) 5 (100%) 2-monthly 9 (19%) 2 (18%) 0 0 3-monthly 2 (4%) 1 (9%) 0 0 Still on treatment Yes, n (%) 2 (4%) 1 (9%) 2 (11%) 1 (20%) No, n (%) 46 (96%) 10 (91%) 17 (89%) 4 (80%) Stop reason Tumour progression 15 (33%) 6 (60%) 1 (6%) 0 Toxicity 22 (48%) 2 (20%) 13 (76%) 2 (50%) Vismodegib as neoadjuvans 4 (9%) 1 (10%) 0 0 Patient died 0 1 (10%) 0 0 No therapy compliance 2 (4%) 0 0 0
Physician fears development of resistance
2 (4%) 0 0c 0
End of trial 1 (2%) 0 3 (18%) 2 (50%)
Median duration of follow-up from the start of vismodegib treatment, months (range)
24.6
(1.8–83.4) 15.2(1.6–40.3) 54.7(1.8–68.5) 32.4(2.8–65.8)
laBCClocally advanced basal cell carcinoma, mBCC metastatic basal cell carcinoma, BCNS basal cell nevus syndrome, BCC basal cell carcinoma.
aPercentages can add up to >100% because a patient can have had various
previous treatments.
bFor the specific indication and which was started in the Netherlands. c
Six following sequences were ended because the physician feared development of resistance.
vismodegib, the probability of partial response was 52.0% (95% CI,
25.5–83.9).
The main reason for treatment discontinuation was tumour
progression (n= 6). Only one patient achieved a complete
response, which currently lasts for >2 years without treatment. This patient only had a regional lymph node metastasis and received previous surgical treatment of the primary BCC. After progressive disease, two patients were treated with radiotherapy, one with surgery, two with anti-programme death-1 inhibitors, two are not treated yet, and three patients died.
Multiple BCCs in BCNS
Nineteen BCNS patients received vismodegib for multiple BCCs. At the start of vismodegib treatment, the median age was 46 years (35–71 years). One patient had previously been treated with vismodegib for this indication abroad and two patients received vismodegib previously for a laBCC, leaving 16 patients for the
effectiveness analysis. Median PFS was 19.1 months (95% CI,
7.4–20.2). Numbers were too small to compare effectiveness in
clinical trial and daily practice patients. In one patient, the time of response was unknown. In the remaining 15 patients, the probability of achieving partial response within 3 months after
the start of vismodegib was 93.3% (95% CI, 74.0–99.6) and
probability of complete response after 6 months of treatment was
40.8% (95% CI, 19.3–72.2). The main reason for treatment
discontinuation was toxicity (n= 13).
Twelve patients (63%) received≥2 treatment sequences, with a
maximum of four sequences (Fig.1). The median treatment break
duration was 11.2 months (range 2.2–54.2 months). All patients responded to vismodegib in all the following sequences. Multiple BCCs in non-BCNS patients
Notably,five non-BCNS patients received vismodegib for multiple
BCCs: three xeroderma pigmentosum patients and two HF-BCC
a 48 01234567891011 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Months 37 38 39 40 41 42 43 44 45 46 47 48 0 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 P a tients 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 5 4 3 2 1 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 Vismodegib treatment Partial response Complete response Progressive disease Surgery Radiotherapy Checkpoint inhibitor
Start new sequence for other indication Patient refused other treatment Death
Last date of information Dosage change to 150 mg every other day
Fig. 1 Continued.
Eight years of experience with vismodegib for advanced and multiple basal. . . BJA Verkouteren et al.
patients (Fig.1). Numbers were too small to perform effectiveness
analyses. Reasons for termination of treatment were toxicity (n=
2) and end of trial (n= 2). One HF-BCC patient has been treated
successfully alternating 3 months on and off vismodegib 150 mg daily for >3 years.
Safety analysis
In total, 409 TEAEs were noted in all sequences (Table 4). Of
those TEAEs, 77% were grade 1 or 2, 2.5% were grade 3 and only 1 patient experienced a grade 4 TEAE (liver toxicity); for the
other TEAEs, the grade was not mentioned in the medicalfile. All
patients experienced at least one TEAE, with a median number
of four TEAEs per patient (range, 1–12 TEAEs) in the first
treatment sequence. Patients who restarted treatment experi-enced the same TEAEs as in the previous sequence. Of all the side effects, 42% resolved, 19% was still present at the last control and for 39% this information was not noted in the
patientfile.
DISCUSSION
In this retrospective cohort study, data were provided about vismodegib use in the Netherlands. In the national guidelines, the
indication for vismodegib treatment is“reserved only for patients
with an aBCC where surgery and radiotherapy are ineffective or
encounter major objections”. In a population of ~17.2 million
people and a suspected incidence of BCC of 3–10% per year, only
80 patients have been treated with vismodegib in a period of
almost 8 years.10,11 Over one-third of these 80 patients were
initially included in a clinical trial, which indicates the reluctance to prescribe vismodegib in the Netherlands.
Unique for our study is the reflection of all data concerning the
use and effectiveness of vismodegib and the course of treatment after vismodegib discontinuation. We found a median PFS of 10.3 months for the indicated laBCC, 11.7 months for mBCC, and 19.1 months for BCNS. Comparable results for the aBCC population were found in other studies. The ERIVANCE trial found a median PFS of 12.9 months for the laBCC group and 9.3 months
42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 Months 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 P a tients 11
150 mg every other day
Head & regional lymph node No previous therapy
Previous surgery primary basal cell carcinoma
Previous vismodegib & surgery primary basal cell carcinoma
Previous vismodegib, radiotherapy, nivolumab and surgery of primary basal cell carcinoma
Vismodegib treatment Checkpoint inhibitor Dosage change Partial response Complete response Progressive disease Surgery Radiotherapy Death
Last date of information Location
primary basal cell carcinoma & histological confirmed metastasis b
Extermity & bone
Head & lung
Head & lung
Head & lung
Head & lung + bone
Trunk & lung Trunk & lung Trunk & distant lymph node
Trunk & regional lymph node
Extremity & regional lymph node
150 mg 6 weeks on and off therapy
0 70 69 68 67 66 65 64 63 62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 Months P a tients 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Achieved complete response, unknown at what time
150 mg 3 months on and off treatment
150 mg every other day 150 mg every other day
Vismodegib treatment Partial response Complete response Progressive disease Last date of information 15 16 17 18 19 20 21 22 23 24 c 0
Fig. 1 Swimmer plots of all individual patients per treatment indication. Time is shown on the horizontal axes in months and individual patients are shown on the vertical axes. a Swimmer plot of locally advanced basal cell carcinoma patients. Patients 14, 21, 22 and 23 received vismodegib as neoadjuvant therapy. Patients 8, 20, 28, 31 and 43 are basal cell nevus syndrome patients. b Swimmer plot of metastatic basal cell carcinoma patients. c Swimmer plot of multiple basal cell carcinoma patients. Patients 20 and 21 are high-frequency basal cell carcinoma patients; patients 22, 23 and 24 are xeroderma pigmentosum patients.
for the mBCC group, and the STEVIE trial found 13.2 months for
the mBCC group.6,12 However, there was one exception, the
STEVIE trial found a much longer PFS of 23.2 months in the laBCC group. The long duration of PFS in the laBCCs of the STEVIE trial is remarkable. An explanation might be a difference in included tumour types between our country and the STEVIE trial. Information on the subtype and size of BCCs included in the STEVIE trial is not available. In our country, vismodegib was exclusively prescribed after evaluation of the tumour in a
multidisciplinary tumour board, including a head and neck surgeon, a radiotherapist and an oncologist, which may result in
defining a tumour “irresectable and not suitable for radiotherapy”
at a more advanced stage. It can be speculated that tumours with a more advanced nature do worse and will show progression at an
earlier stage. This hypothesis is confirmed by analyses of our own
data in which we found that larger tumours have a lower probability of complete response versus smaller tumours. A second explanation for the difference in PFS between our study and the STEVIE can be the retrospective nature of our study in which effectiveness outcomes relied on the accuracy of record keeping and the frequency of patient visits. Less meticulous measurements in daily practice might affect the assessed PFS. Finally, the definition of tumour progression differed between the studies: in the STEVIE trial, it was defined as >20% increase in size, taking as reference the smallest tumour size measured during the study, whereas in our study, progression as noted by the physician
was additionally defined as disease progression. In the latter
definition of progression, the increase could be <20%, but with
more other complaints, such as bleeding, pain or ulceration. This could have led to a shorter PFS in our study.
A few patients achieved a prolonged complete response, a phenomenon that has previously been described in a French
population.13 To determine what tumour types achieved a
complete response, we compared several factors for probability of complete response in the multivariable Cox regression analysis (tumour size, histologic subtype, previous treatment and clinical trial participation). Irrespective of the other variables, patients with laBCCs that participated in the STEVIE trial had a very high probability of achieving a complete response compared to patients treated in daily practice. This higher effectiveness of treatments in patients participating in randomised controlled trials
is known as the Hawthorne effect.14
According to the FDA (United States Food and Drug Adminis-tration) and EMA (European Medicines Agency) guidelines, vismodegib is only approved for the treatment of aBCC. Data on effectiveness for other indications are sparse and no such data are expected in the near future as there are currently no such clinical trials registered. In our cohort, 22 patients (26%) received vismodegib for a multiple BCC indication (20% BCNS, 4% XP and 2% HF-BCC patients). The large number of BCCs places a heavy burden on these patients and a therapy that can treat all
lesions at once is very desirable.15 In line with previous clinical
trials, we found a high effectiveness of vismodegib in this patient population, but the majority of patients discontinued due to side effects. The frequency of most side effects was somewhat lower
than in the STEVIE and ERIVANCE trials.6,16A possible explanation
is the retrospective nature of our study. Also, the shorter treatment duration could be causative, as it was found in the STEVIE trial that the frequency of most side effects increased with
the treatment duration.6Two differences in side effects compared
to previously published trials are notable: (1) a very low frequency of weight loss (28 vs. 41%) and (2) a higher frequency of dysgeusia
(72 vs. 55%).6Weight measurement was obligatory in the STEVIE
trial, but sometimes omitted in real life, which can explain the difference in the frequency of weight loss. We cannot explain the higher frequency of dysgeusia. However, we hypothesise that its inconvenience stresses patients more to mention this at their
consultation, even if not specifically asked for, whereas in the
STEVIE trial, all side effects had to be checked systematically. To allow patients to recover from side effects, different intermittent dosing schedules were used. In the two intermittent vismodegib dosing regimens of the MIKIE trial (vismodegib daily alternate with 8 weeks of placebo), side effects still appeared
substantial.8From our data, it becomes clear that in daily practice
patients often have a much longer treatment break. Although our data show a lower frequency of side effects in the following sequences, it does not mean patients will endure less side effects
1.00
a
b
c
Progression-free survival by indication
Partial response by indication
Complete response by indication
0.75 0.50 0.25 0.00 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 0.25 0.00 Number at risk Indication = laBCC
Indication = laBCC Indication = mBCC
Indication = mBCC Indication = BCNS
Indication = BCNS
Indication = laBCC Indication = mBCC Indication = BCNS
Indication = laBCC Indication = BCNS
44 10 16 Number at risk Indication = laBCC Indication = mBCC Indication = BCNS Number at risk Indication = laBCC Indication = BCNS 44 15 44 15 42 13 37 12 29 9 25 8 15 5 9 4 8 4 7 4 5 3 5 3 4 1 44 10 15 24 8 8 12 5 3 2 4 1 2 2 1 1 1 0 0 0 0 40 9 15 31 8 13 23 5 9 17 3 8 15 2 7 14 1 7 12 1 1 10 1 1 0 0 1 2 3 4 5 6 3 6 9 12 Months Months 0 1 2 3 4 5 6 7 8 9 10 11 12 Months 15 18 21 24
Fig. 2 Kaplan-Meier curved of time-to-event analyses per treatment indication. (a) Progression-free survival by indication. (b) Partial response by indication. (c) Complete response by indication.
Eight years of experience with vismodegib for advanced and multiple basal. . . BJA Verkouteren et al.
in the following sequence. As most patients stopped treatment due to side effects, selection of patients who have experienced less severe side effects could have occurred in the group that was treated with a second sequence. Moreover, the median treatment durations of the following sequences were shorter compared to
the first sequence (6.4 months in the first, 5.3 months in the
second, 3.3 in the third and 4.8 in the fourth sequence). From the STEVIE trial, it is known that the median time to onset of alopecia is 5.6 and dysgeusia is 6.5 months, which might explain why those
side effects were reported less in the second sequence.7Lastly,
~20–30% of the patients in the following sequence received an
alternate dose of vismodegib, specifically to lower side effects.
Seven BCNS patients have already been treated successfully for ≥3 times in 8 years and one HF-BCC patient is treated successfully for years with 3 months on and off vismodegib treatment. Unfortunately, there is currently no information on the effects of lifelong intermittent treatment on the general health of patients and on the progression of BCC size and aggressiveness during treatment breaks. Although it is likely that intermittent vismode-gib and multiple surgical procedures both affect the quality of life in this patient group, it is currently unknown which strategy has the least impact. Clustering data from different BCNS centres worldwide can provide the best answers to these questions.
This study provides important information on vismodegib effec-tiveness and the course of treatment after vismodegib discontinua-tion. Median PFS was less than a year for aBCCs. Future research should focus on treatment combinations or options after vismodegib
failure and defining which patients can achieve a prolonged
complete response. In BCNS patients, PFS is longer than in aBCCs, but treatment is often discontinued due to side effects. Retreatment remains effective and can be applied in various schedules.
AUTHOR CONTRIBUTIONS
Conception and design: B.J.A.V., R.-J.A., and K.M. Data acquisition: B.J.A.V., R.-J.A., K.M., M.W., A.K.L.R., M.J.B.A., E.R., J.B.T., L.A.D., E.K., R.v.D., and M.W.B. Statistical analyses: B.J. A.V., P.N., and K.M. Original draft of the manuscript: B.J.A.V., M.W., M.G.H.C.R., A.K.L.R., P.N., and K.M. Revising manuscript: B.J.A.V., M.W., A.K.L.R., P.N., M.J.B.A., E.R., J.B.T., L.A. D., R.-J.A., E.K., R.v.D., M.W.B., M.G.H.C.R., and K.M. Final manuscript: B.J.A.V., M.W., A.K. L.R., P.N., M.J.B.A., E.R., J.B.T., L.A.D., R.-J.A., E.K., R.D., M.W.B., M.G.H.C.R., and K.M. Supervising role: K.M.
Table 3. HR with 95% CI for complete response in locally advanced basal cell carcinoma associated with patient and tumour
characteristics (n= 44). Characteristic HR with 95% CI univariable analysis Pvalue HR with 95% CI multivariable analysis Pvalue
Age (per year)a 0.99 (0.96–1.03) 0.85 Sex
Male 1.00
Female 1.78 (0.63–5.07) 0.28 Tumour size (per
cm)b 0.91 (0.79–1.06) 0.24 0.77 (0.62–0.95) 0.02 Tumour location
Not on the head 1.00 0.86
On the head 0.90 (0.25–3.18) Tumour subtype Non-infiltrative 1.00 0.16 1.00 0.06 Infiltrative 0.46 (0.16–1.35) 0.21 (0.04–1.08) Bone invasion No 1.00 0.67 Yes 0.78 (0.25–2.46) Previous therapy No 1.00 0.44 1.00 0.22 Yes 0.44 (0.24–1.86) 0.46 (0.13–1.58) Previous radiotherapy No 1.00 0.61 Yes 1.40 (0.39–5.06) Participant in trial No 1.00 0.09 1.00 <0.01 Yes 2.38 (0.86–6.58) 10.08 (2.14–47.43) HRs for complete response with 95% CI in patients with laBCC.
HR > 1 and HR < 1 indicate increased and decreased probability of response, respectively, where categories with HR= 1 were used as the reference category. P < 0.05 is considered statistically significant. HRshazard ratios, 95% CI 95% confidence interval.
a
The HR for age represents the increase in probability per year.
bThe HR for tumour size represents the increase in probability per cm.
Table 2. Time-to-event anayses of progression and response endpoints.
Indication/endpoint 1 month (95% CI) 3 months (95% CI) 6 months (95% CI) 12 months (95% CI) Median time to (95% CI)
Median duration of response (95% CI)a laBCC PFS overall 100.0 90.9 (77.6–96.5) 74.5 (58.6–85.0) 44.6 (29.1–58.9) 10.3 (7.5–22.6) NA PFS STEVIE 100.0 93.3 (61.3–99.0) 86.7 (56.4–96.5) 60.0 (31.8–79.7) 13.6 (6.1–26.6) NA PFS daily practice 100.0 89.7 (71.3–96.5) 67.8 (47.1–81.8) 35.4 (17.8–53.6) 10.2 (5.6–22.6) NA Partial response 45.5 (32.2–61.2) 94.6 (84.4–99.0) NR NR 1.1 (0.9–1.8) 9.7 (6.7–19.9)b
Complete response 0.0 7.1 (2.3–20.4) 33.9 (20.6–52.5) 51.9 (33.2–73.5) 7.4 (5.8–NE) 10.3 (4.5–22.1) mBCC PFS 100.0 100.0 88.9 (43.3–98.4) 33.3 (7.8–62.3) 11.7 (5.2–17.5) NA Partial response 20.0 (5.4–59.1) 52.0 (25.5–83.9) NR NR 2.5 (0.9–4.2) 9.2 (3.2–14.5)b Complete response NA NA NA NA NA NA BCNS PFS 100.0 100.0 100.0 61.5 (30.8–81.8) 19.1 (7.4–20.2) NA Partial response 46.7 (25.6–73.7) 93.3 (74.0–99.6) NR NR 1.0 (0.9–1.7) 11.3 (5.0–18.8)b Complete response 0.0 7.7 (1.1–43.4) 40.8 (19.3–72.2) 88.2 (59.8–99.3) 6.4 (3.9–11.0) 8.3 (2.8–16.3)
Cumulative probability of PFS, partial response and complete response with 95% CI, median time to endpoint with 95% CI and median duration of any and complete response with 95% CI.
PFSprogression-free survival, 95% CI 95% confidence interval, NA not applicable, NR no more responders, NE not estimable.
aAnalysis based on responders only. b
Median duration of any response.
ADDITIONAL INFORMATION
Ethics approval and consent to participate This study was approved with a waiver of informed consent by the Medical Ethics Committee of all participating centres (see Supplementaryfile, Ethics Committees). This study was performed in accordance with the Declaration of Helsinki.
Data availability Data are not available in a public database yet, but authors are willing to share data.
Competing interests The authors declare no competing interests. Funding information None.
Supplementary information is available for this paper athttps://doi.org/10.1038/ s41416-020-01220-w.
Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Table 4. TEAEs per treatment sequence.
TEAEs, n Sequence 1, n= 78a Sequence 2,
n= 22a
Sequence 3, n= 8
Sequence 4, n= 5
Resolved Not resolved Not reported
Muscle spasms, 81 58 (74%) 14 (64%) 7 (88%) 2 (40%) 35 (43%) 12 (15%) 34 (42%) Dysgeusia, 76 56 (72%) 14 (64%) 4 (50%) 2 (40%) 35 (46%) 13 (17%) 28 (37%) Alopecia, 55 47 (60%) 6 (27%) 2 (25%) – 24 (44%) 9 (16%) 22 (40%) Weight loss, 29 22 (28%) 5 (23%) 2 (25%) – 7 (24%) 5 (17%) 17 (59%) Fatigue, 21 19 (24%) 1 (5%) 1 (13%) – 4 (19%) 9 (43%) 8 (38%) Decreased appetite, 17 12 (15%) 4 (18%) 1 (13%) – 8 (47%) 6 (35%) 3 (18%) Diarrhoea, 15 11 (14%) 2 (9%) 1 (13%) 1 (20%) 6 (40%) 1 (7%) 8 (53%) Nausea, 13 9 (12%) 3 (14%) 1 (13%) – 6 (46%) 1 (8%) 6 (46%) Headache, 9 9 (12%) – – – – – – Myalgia, 8 7 (9%) 1 (5%) – – – – – Hepatotoxicity, 6 4 (5%) 2 (9%) – – – – – Dizziness, 6 5 (6%) 1 (5%) – – – – – Abdominal pain, 4 4 (5%) – – – – – – Ageusia, 4 4 (5%) – – – 1 (25%) – 3 (75%) Asthenia, 2 2 (3%) – – – – – 2 (100%)
TEAEtreatment-emergent adverse event.
aAll individual patients who received thefirst or second treatment sequence in the Netherlands.
Eight years of experience with vismodegib for advanced and multiple basal. . . BJA Verkouteren et al.
